HIV infection causes a broad range of pathologic processes. One of the most important late stage complications of HIV infection is known as AIDS dementia complex or HIV-associated encephalitis. This is a pathologic process that is characterized by frank memory loss, social withdrawal, alterations in personality and the inability to perform normal daily living activities.
The pathologic processes that characterize AIDS dementia include astrocytosis (thought in part to be secondary to factors causing toxic damage to the brain), multinucleated giant cell formation, microglial nodule formation, and frank neural cell death. All of these changes are seen in the context of HIV-infected macrophage infiltration both perivascularly as well as into the brain parenchyma. In certain studies, the frequency of the HIV-expressing macrophage was associated with the degree of dementia. Virtually all patients with advanced dementia have extremely high levels of HIV in the brain, and this virus is almost always associated with brain macrophages or microglial cells as neuron and astrocytes have rarely, if ever, been documented as being infected in-vivo by HIV.
Although the mechanism by which HIV causes dementia is unclear, many studies implicate macrophages as playing a pivotal role in the dementia process through the elaboration of neurotoxic substances. One of the principal substances implicated in the pathogenesis of AIDS dementia is tumor necrosis factor (TNF-.alpha.). Macrophages release TNF-.alpha. and other cytokines in response to stimulus of the immune system. It is a critical component of the cell mediated immune response to infections. TNF-.alpha. is expressed in response to bacterial and viral immunostimulators, and particularly in response to HIV infections, and has been shown to cause damage to brain cells in vitro.
TNF-.alpha. also manifests a dose dependent toxicity in other tissues. At chronic levels, TNF-.alpha. can cause cachexia and at acute levels can cause septic shock. Prior art methods for suppressing TNF-.alpha. rely on antiinflammatory and immunosuppressive steroids. However, such steroids also suppress other cytokines necessary for proper cell mediated response.
The prior art offers no treatment for patients suffering from AIDS dementia. Since dementia affects 20%-30% of AIDS patients, there is a substantial need for an effective treatment. Furthermore, there is a need for controlling TNF-.alpha. levels while minimizing the effects on other cytokines. This invention satisfies these and other needs.